Morphine has a serum half-life of 2-4 hours and the duration of its analgesic effect is about 4-6 hours after oral administration.
The short duration makes it necessary to administer morphine orally 4-6 times daily to achieve a satisfactory analgesic effect.
This has led to a development of various oral controlled release formulations of morphine.
Oral controlled release products containing morphine on the market e.g. MST Continus.RTM. or MS Contin.RTM. and Dolcontin.RTM., are in general administered 2-3 times a day in order to give a sufficient pain relief over the entire dosage interval. Conventional matrix tablets consisting of morphine and an inert carrier composition are characterized by a fast initial drug release leading to an early peak of morphine plasma concentration followed by a decrease in release, which will be especially pronounced in the lower intestinal system where more neutral or weakly basic conditions prevail.
There has been a demand to find a way to obtain an oral drug preparation having a more even release of morphine in order to get smoother blood concentration and effect profiles over the entire dosage interval when administered once daily.
EP-B-0 097 523 discloses such a preparation where the drug is distributed in a controlled release matrix partly in the form of a salt and partly as a free base. This preparation increases dissolution time and biovailabilty without the need of applied coating membranes.
It is known that morphine gives considerable problems in the development of matrix tablets which have been considered to be due to poor absorption properties of morphine in the distal parts of the gastrointestinal tract, see Proceed. Intern. Symp. Control. Rel. Bioact. Mater., 18, 1991, pag. 433-434, (B. Olsson et al).
There are several examples of formulations which are designed to overcome the drawbacks of oral matrix tablets by providing a constant or controlled release rate over a more extended period.
An example of such formulations is multiple unit (MU) formulations as disclosed previously in EP-A-0 080 341 and in WO-A-91/01722.
The depot preparation consisting of a large number of small units is considered to promote good absorption properties by being dispersed over a large area in the gastrointestinal tract and having a lower transit rate especially in the colon, compared to matrix tablets, see Drug Delivery to the Gastrointestinal Tract, Ed. By J. G. Hardy Et. al., Chichester, Ellis Howard Ltd, 1989, pages 75-81: "Colonic transit rate and drug delivery". In addition multiple unit formulations are preferable to one single unit as they may be divided into smaller portions all having the same release and absorption properties which will give greater flexibility in selection of the size of the dose, will facilitate administration of the drug to patients having problems to swallow and will considerably reduce the risk of dose dumping.
Also in EP-A-0 377 518 there is described a sustained release pellet formulation, but with core elements which may comprise the salt of a morphine compound coated with a hybrid coating admitting a slow release at an acidic pH and relatively constant higher release at a less acidic to basic pH. The preparations according to EP-A-0 377 518 exhibit a limited bioavailibility, restricting the administration to at least twice daily.
ZA-A-921366 relates to a solid controlled release dosage form for improved storage stability at elevated temperature and/or elevated relative humidity. The controlled release is obtained by overcoating a substrate including a therapeutically active ingredient with a coating derived from an aqueous dispersion of ethylcellulose and then curing the coated substrate at an elevated relative humidity and at a temperature above the glass transition temperature for the coating. There is no indication in ZA-A-921366 that any of the preparations would be suitable for a once daily administration.